The glomerular filtration rate (GFR) is the established measurement of kidney function that is used to define the presence and severity of chronic kidney disease (CKD). The diverse physiological functions of the kidneys are unlikely to be captured by GFR alone. Proximal tubule secretion is an essential, kidney-specific mechanism for rapidly eliminating retained solutes and administered medications from the circulation. We developed and validated novel assays to measure endogenous markers that are primary cleared by proximal tubule secretion. We used these markers to demonstrate considerable individual-level variability in estimated tubule secretion function relative to GFR among CKD patients. This grant proposes two parallel aims to advance understanding of proximal tubule secretion function. First, we will estimate secretion function in the prospective Chronic Renal Insufficiency Cohort study and determine associations with CKD complications and major clinical outcomes. Second, we will recruit a primary cohort of patients across a broad range of kidney function and compare estimated tubule secretion function versus GFR for predicting renal drug clearances. Potential applications of the proposed studies include earlier detection of CKD, improved monitoring of kidney disease patients, and optimized renal medication dosing strategies.